Causal relationship between inflammatory skin diseases and breast cancer: A bidirectional Mendelian randomization study

Abstract Introduction Prior research has explored the relationship between inflammatory skin disorders and breast cancer (BC), yet the causality of this association remains uncertain. Methods Utilizing a bidirectional two‐sample Mendelian randomization (MR) approach, this study aimed to elucidate the causal dynamics between various inflammatory skin conditions—namely acne, atopic dermatitis, psoriasis vulgaris, urticaria, and rosacea—and BC. Genetic variants implicated in these disorders were sourced from comprehensive genome‐wide association studies representative of European ancestry. In the forward MR, BC was posited as the exposure, while the reverse MR treated each inflammatory skin disease as the exposure. A suite of analytical methodologies, including random effects inverse variance weighted (IVW), weighted median (WME), and MR‐Egger, were employed to probe the causative links between inflammatory skin diseases and BC. Sensitivity analyses, alongside evaluations for heterogeneity and pleiotropy, were conducted to substantiate the findings. Results The MR analysis revealed an increased risk of acne associated with BC (IVW: OR = 1.063, 95% CI = 1.011–1.117, p = 0.016), while noting a decreased risk of atopic dermatitis (AD) in BC patients (IVW: OR = 0.941, 95% CI = 0.886–0.999, p = 0.047). No significant associations were observed between BC and psoriasis vulgaris, urticaria, or rosacea. Conversely, reverse MR analyses detected no effect of BC on the incidence of inflammatory skin diseases. The absence of pleiotropy and the consistency of these outcomes strengthen the study's conclusions. Conclusion Findings indicate an elevated incidence of acne and a reduced incidence of AD in individuals with BC within the European population.


INTRODUCTION
The mounting evidence indicates a significant correlation between inflammation and the development of cancer.However, the association between inflammatory diseases and systemic malignancies remains unclear. 1,2Inflammatory skin diseases are characterized by chronic inflammation, immune dysregulation, and altered cytokine profiles. 3ronic inflammation has been recognized as a hallmark of cancer, contributing to tumor initiation, promotion, and progression. 4In particular, the pro-inflammatory cytokines and chemokines released during chronic skin inflammation may create a microenvironment conducive to carcinogenesis. 5For example, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), which are elevated in psoriasis and atopic dermatitis, have been implicated in the development and progression of breast cancer. 6,7east cancer is the most common malignancy among women worldwide, despite advances in early detection and treatment, breast cancer remains a significant public health burden, necessitating the identification of novel risk factors and potential preventive strategies. 8,9In recent years, increasing evidence has suggested a link between inflammatory skin diseases, such as psoriasis and rosacea, and various cancers, including breast cancer. 10,11idemiological studies have reported associations between inflammatory skin diseases and breast cancer risk.A cohort study by Yang et al. 12 found that patients with breast cancer had a significantly increased risk of psoriasis vulgaris (hazard ratio [HR] = 1.33, 95% confidence interval [CI]: 1.17-1.52).Furthermore, another study in southern China by Long et al. 11 demonstrated that patients with rosacea had a higher incidence of breast cancer compared to the general population.However, these observational studies are susceptible to confounding factors and reverse causation, making it challenging to establish a causal relationship between inflammatory skin diseases and breast cancer risk.
Mendelian randomization (MR) is a powerful genetic epidemiological approach that utilizes genetic variants as instrumental variables to assess the causal effect of an exposure on an outcome, minimizing the influence of confounding factors and reverse causation. 13By leveraging the random allocation of genetic variants during meiosis, MR mimics the design of randomized controlled trials, providing a more robust assessment of causality. 14[17] To date, no MR study has comprehensively investigated the causal relationship between inflammatory skin diseases and breast cancer risk.Therefore, we conducted a bidirectional two-sample MR study to assess the causal effects of acne, atopic dermatitis, psoriasis vulgaris, urticaria, and rosacea on breast cancer risk, as well as the causal effects of breast cancer on these inflammatory skin diseases.By employing a bidirectional design, we aimed to provide insights into the complex interplay between these conditions and unravel potential shared genetic and biological mechanisms.

Study design
We conducted ten Mendelian randomization analyses using publicly available genome-wide association studies (GWASs) with singlenucleotide polymorphisms (SNPs) significantly associated with exposure as instrumental variables.Mendelian randomization relies on three core assumptions: association, independence, and exclusivity.
First, the instrumental variables must be strongly associated with the exposure factor.Second, the instrumental variables must not be associated with confounding factors that correlate with the outcome.Third, the instrumental variables must affect the outcome only through the exposure factor and not via other pathways. 18The analysis flow is depicted in Figure 1.

Data sources
This analysis encompasses GWAS to investigate the genetic determinants of breast cancer and various inflammatory dermatologic conditions.Summary data from the IEU Open GWAS project provided the basis for examining associations within a cohort of 17 389 breast cancer cases and 240 341 controls. 19

SNP selection
SNPs manifesting strong associations with breast cancer, acne, atopic dermatitis, and psoriasis vulgaris were selected based on a genomewide significance threshold of p < 5 × 10 −8 to satisfy the prerequisites for Mendelian randomization.For urticaria and rosacea, a relaxed significance threshold of p < 5 × 10 −6 was applied.SNPs were further refined by excluding those with linkage r 2 ≥ 0.001 and kb ≥ 10 000 kb to mitigate the effects of linkage disequilibrium.Abbreviation: GWAS, genome-wide association studies.
analysis. 22Instrumental strength was evaluated using the F statistic, with an F-value exceeding 10 denoting robust tool validity and diminishing the risk of weak instrumental bias.SNPs failing to meet this standard were omitted from subsequent analysis. 23Comprehensive details pertaining to these instrumental variables are cataloged in Tables S1-S10.

Statistical analyses
The IVW model served as the foundational analytical approach, augmented by WME and MR-Egger regression for the derivation of effect estimates.These estimates were converted to odds ratios (ORs) to elucidate potential causal linkages.Sensitivity analyses, employing MR-Egger and MR-PRESSO tests, were conducted to interrogate the presence of horizontal pleiotropy, alongside the exclusion of outliers from the instrumental variable set.Heterogeneity was explored via Cochran's Q test, and the leave-one-out method was applied to verify the robustness of the findings. 24,25Following Bonferroni adjustment, results with p-values less than 0.01 (0.05/5) were deemed statistically significant, whereas associations with p-values equal to or greater than 0.01 but less than 0.05 were considered to be suggestive. 26
Sensitivity analyses across a range of models yielded no evidence of significant bias.MR-Egger regression did not provide any indi-F I G U R E 2 Association of BC with the risk of acne, atopic dermatitis, psoriasis vulgaris, urticaria, and rosacea in forward Mendelian randomization analyses.Causal inferences are presented in the form of odds ratios along with 95% CIs.Following the application of a Bonferroni correction, an alpha threshold of 0.01 (α = 0.05/5) was established as the criterion for discerning significant associations.Associations yielding p-values equal to or greater than 0.01 but less than 0.05 were interpreted as indicative of suggestive significance.BC, breast cancer; CI, confidence intervals; IVW, inverse variance weighted; nSNP, the number of SNPs.

Causal effect of inflammatory skin diseases on BC
In the context of reverse MR analysis, 12 SNPs for acne, 18 for atopic dermatitis, 9 for psoriasis vulgaris, 13 for urticaria, and 12 for rosacea were utilized as instrumental variables in the final analysis.The Mendelian randomization analysis, employing a random-effects IVW model, revealed no significant genetic correlation between breast cancer risk and the inflammatory skin conditions assessed.The odds ratios were as follows: for acne, OR = 1.080 (95% CI: 0.988-1.181,p = 0.089); for atopic dermatitis, OR = 1.007 (95% CI: 0.955-1.061,p = 0.798); for psoriasis vulgaris, OR = 1.016 (95% CI: 0.987-1.046,p = 0.282); F I G U R E 3 Association of acne, atopic dermatitis, psoriasis vulgaris, urticaria, and rosacea with the risk of BC in reverse Mendelian randomization analyses.Causal inferences are presented in the form of odds ratios along with 95% confidence intervals.Following the application of a Bonferroni correction, an alpha threshold of 0.01 (α = 0.05/5) was established as the criterion for discerning significant associations.Associations yielding p-values equal to or greater than 0.01 but less than 0.05 were interpreted as indicative of suggestive significance.BC, breast cancer; IVW, inverse variance weighted; nSNP, the number of SNPs.Moreover, the analysis hinted at a reduced likelihood of atopic dermatitis development in breast cancer patients, yet no substantial evidence emerged to affirm an inverse causal linkage, that is, atopic dermatitis contributing to an increased risk of breast cancer.

Variable
The observed association between acne and the etiopathogenesis of breast cancer points to shared genetic and biological pathways.
The immune system's role is hypothesized to be pivotal, with chronic inflammation being a common denominator in the pathophysiology of both conditions.Inflammation is recognized as contributory to tumorigenesis, progression, and metastasis in breast cancer, 27 while acne is marked by inflammation within sebaceous glands and elevated levels of proinflammatory cytokines, including interleukin-17 and tumor necrosis factor-alpha. 28The inflammatory state linked to breast cancer may thus foster conditions amenable to acne development.Another potential mechanism could involve the hormonal interplay, particularly the role of androgens, represents another intersecting factor in both pathologies.Androgens, such as testosterone and dihydrotestosterone, are known to augment sebum production and precipitate acne, 29 whereas their influence on breast cancer remains an area of debate and ongoing research. 30Hormonal fluctuations pertinent to breast cancer could also modulate acne manifestation.
Furthermore, the management of breast cancer with chemotherapeutic and targeted therapies introduces additional variables.These interventions are accompanied by a spectrum of dermatological side effects and immune perturbations, potentially leading to acneiform manifestations. 31Notably, epidermal growth factor receptor (EGFR) inhibitors, commonly used in the treatment of breast cancer, have been associated with acneiform eruptions. 31The precise mechanisms through which these therapeutic modalities might heighten acne risk warrant further scrutiny.The intricate biological interplay between breast cancer and acne necessitates comprehensive elucidation, underscoring the need for continued research into their interconnected mechanisms.
Investigations in Taiwan and combined studies from the United Kingdom and Denmark evaluated the association between atopic dermatitis and breast cancer risk, yielding standardized incidence ratios (SIR = 1.16, 95% CI: 0.84-1.57)and hazard ratios (HR = 0.97, 99% CI: 0.76-1.24),respectively; neither study demonstrated a significant correlation. 32,33Contrarily, our analyses suggest a decreased incidence of atopic dermatitis among patients with breast cancer, intimating a potential inverse relationship.This Mendelian randomization study contributes novel insights into a possible protective effect of breast cancer against atopic dermatitis.The biological mechanisms underlying this inverse association warrant further exploration.One possible explanation is the role of estrogen in both breast cancer and atopic dermatitis.Atopic dermatitis is typified by heightened immune responses and an upsurge in Th2 cytokines such as interleukin-4 and interleukin-13, in concert with Th1, Th17, and IgE secretion. 34,35Estrogen is a well-established risk factor for breast cancer, promoting cell proliferation and tumor growth through its actions on estrogen receptors (ERs). 36Specifically, estrogen may downregulate Th1 and Th17 responses, a pivotal element in atopic dermatitis pathogenesis, though its precise role remains a subject of debate. 37Furthermore, genetic factors may also contribute to the inverse association between breast cancer and atopic dermatitis.Some studies have identified certain genetic loci associated with both diseases.For example, variants in the filaggrin gene (FLG), which is integral to skin barrier function, exhibit a robust association with atopic dermatitis, and null mutations in FLG correlate with an augmented risk of the condition. 38,39tably, Adnane et al. discovered amplifications of the FLG gene within tumor DNA from patients with breast cancer, hinting at a potential shared genetic foundation for the inverse correlation between these entities. 40However, more research is needed to elucidate the specific genetic mechanisms underlying this association.The reduced risk of atopic dermatitis in breast cancer patients suggests that the presence of atopic dermatitis may be a potential protective factor against breast cancer development.This information could be valuable for risk stratification and personalized prevention strategies.
The examination of potential causal links between psoriasis vulgaris, urticaria, or rosacea and breast cancer risk yielded no significant relationships.This outcome intimates that the associations between these dermatological conditions and breast cancer might be tenuous or obscured by factors not accounted for in this Mendelian randomization analysis.Previous observational studies have presented mixed findings.A meta-analysis indicated an increased breast cancer risk associated with psoriasis (Relative Risk [RR] = 1.088, 95% CI: 1.026-1.153), 41and separate research in China found an elevated incidence of breast cancer among patients with rosacea (Odds Ratio [OR] = 5.00, 95% CI: 4.02-6.20). 11The current MR study, by minimizing confounding and reverse causation, provides a robust assessment of causality.
Several factors might account for the absence of a causal relationship.Firstly, the pathogenesis of these inflammatory skin disorders and breast cancer diverges significantly.Breast cancer is largely influenced by hormonal fluctuations, genetic susceptibility, and lifestyle, 42 whereas the dermatoses in question emerge from intricate interplays between immune responses, skin barrier integrity, and environmental triggers. 43Despite chronic inflammation being a common thread in the pathogenesis of both breast cancer and the investigated skin conditions. 27Secondly, the genomic landscapes of breast cancer and the aforementioned skin conditions differ markedly.Genome-wide association studies (GWAS) have pinpointed distinct genetic loci linked with each disease.For instance, mutations in the BRCA1 and BRCA2 genes are well-established risk factors for breast cancer, 44 while mutations in the caspase recruitment domain family member 14 gene (CARD14) are significantly associated with psoriasis. 45This divergence in genetic determinants may elucidate the absence of a causal connection as determined by this analysis.In addition, the interplay between the immune system's function in breast cancer and inflammatory skin diseases is intricate and varies according to context.Inflammatory skin disorders are characterized by immune dysfunction, and the immune system's role in breast cancer is paradoxical, providing both tumorigenic and tumoricidal effects. 46The equilibrium of these opposing actions likely shifts with the cancer's subtype and stage, as well as the individual's immune profile, potentially explaining the absence of a causal link in the current analysis.
The methodological strengths of this study include a bidirectional MR approach for evaluating causality in both directions, thus enrich-ing the understanding of the interrelation between inflammatory skin diseases and breast cancer.Leveraging pooled statistics from expansive GWAS through a two-sample MR analysis enhances the power of the investigation while reducing the impact of confounding variables. 47rthermore, the application of various MR methodologies such as inverse variance weighting, weighted median, and MR-Egger regression ensures the robustness of findings and accounts for potential complexities. 48netheless, studying is not devoid of limitations.The MR approach is predicated on assumptions like the non-existence of horizontal pleiotropy and the appropriateness of the genetic instruments employed. 49Despite efforts to address these concerns through multiple MR techniques and sensitivity analyses, the possibility of underlying pleiotropy and instrument invalidity cannot be entirely dismissed.
It is critical to recognize, however, that the lack of observable causal effects does not preclude the existence of such a relationship, as MR analyses have inherent limitations, including the potential for genetic pleiotropy and the selection of instrumental variables.Moreover, the study's focus on a European demographic restricts the extrapolation of results to other populations.

CONCLUSIONS
Conclusively, the bidirectional MR study revealed a positive association between breast cancer and acne and an inverse causal relationship between breast cancer and atopic dermatitis, no evidence was found to support a causal link between breast cancer and psoriasis vulgaris, rosacea, or urticaria.These outcomes underscore the intricate nexus between breast cancer and inflammatory skin conditions and the necessity of integrating various lines of evidence in disease association assessments.They also suggest shared genetic and biological underpinnings between acne and breast cancer, as well as atopic dermatitis and breast cancer, suggesting a conserved etiological nexus across these conditions.The results indicate that psoriasis vulgaris, rosacea, and urticaria should not be deemed risk factors for breast cancer, which could inform risk assessment and clinical management strategies.Nevertheless, the absence of a causal association does not diminish the importance of standard breast cancer screening and surveillance as per clinical guidelines.Future research is imperative to delineate the shared and distinct biological pathways of these conditions and to pinpoint intervention targets.Additionally, these findings serve as a reminder for healthcare providers to be vigilant of the increased incidence of acne in breast cancer patients, advocating for early intervention to enhance quality of life and avert complications.
Understanding the inverse association between breast cancer and atopic dermatitis may provide valuable insights into the development and management of both conditions, ultimately leading to improved patient outcomes and personalized prevention strategies.
Furthermore, analyses using MR-PRESSO failed to uncover outliers or horizontal pleiotropy.The stability of the observed associations was corroborated through exclusion sensitivity analysis, indicating that no individual SNP disproportionately swayed the findings, with supportive visual evidence in Figure S1.Complementary scatter plots that delineate the interrelations between breast cancer and the quintet of dermatological conditions are furnished in Figure S2, providing additional clarity to the results.Evaluation of the funnel plots, as featured in Figure S3, uncovered minimal evidence of bias.

4 DISCUSSION
Utilizing a bidirectional Mendelian randomization framework, this analysis probed into the causal dynamics between inflammatory skin conditions-comprising acne, atopic dermatitis, psoriasis vulgaris, urticaria, and rosacea-and breast cancer risk, delineating the directional underpinnings of these associations.The findings implicate breast cancer as a potential risk factor for the development of acne, with both analytical modalities within the Mendelian randomization framework indicating positive causal inferences, achieving suggestive significance with p-values falling below the 0.05 threshold.Conversely, these investigations did not substantiate a reciprocal causal relationship, specifically that acne may predispose individuals to breast cancer.
Framework of the study design in this bidirectional MR study.BC, breast cancer; MR, Mendelian randomization; SNP, single-nucleotide polymorphism.Mendelian randomization study's relevant information of GWAS database.
SNPs in forward Mendelian randomization analyses.